Current Infectious Disease Reports (2019) 21:53 https://doi.org/10.1007/s11908-019-0707-4

TRANSPLANT AND ONCOLOGY (M ISON, N THEODOROPOULOS AND S PERGAM, SECTION EDITORS)

Diagnosis and Treatment of Acute Invasive Fungal Sinusitis in Cancer and Transplant Patients

Monica Fung1 & Jennifer Babik1 & Ian M. Humphreys2 & Greg E. Davis2

# Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract Purpose of Review Modern advances in oncologic and end-organ therapies have led to an increase in immunocompro- mised patients and a corresponding rise in acute invasive fungal sinusitis (AIFS). Here, we present a comprehensive medical and surgical approach to the diagnosis and management of immunocompromised cancer and transplant patients with AIFS. Recent Findings Aspergillus and Mucorales are the most common fungi to cause AIFS, though atypical fungal pathogens have been implicated particularly among patients on azole prophylaxis. Symptoms present in the majority of AIFS cases include fever, nasal congestion, and facial swelling. Nasal endoscopy and radiology are adjuncts to clinical exam with the gold standard diagnostic test still being histopathology, though molecular testing such as panfungal PCR is playing a larger role. The treatment of AIFS requires surgery, antifungal therapy, and reversal of immunosuppression. We recom- mend initiation of liposomal amphotericin B as an empiric therapy for AIFS, transitioned to targeted therapy when/if a fungal pathogen is identified. Goals of surgery include diagnostic sampling and debridement of necrotic tissue. Equally, if not more important, is reversal of underlying immune suppression. Immune-stimulating therapies hold promise for reducing mortality, but require additional study. Summary Despite improvements in medical and surgical management of AIFS, mortality continues to approach 50%. Early diagnosis of this disease entity followed by aggressive surgical and medical management are important, including reversal of the underlying immunosuppression.

Keywords Acute invasive fungal sinusitis . Transplant . Immunocompromise

Introduction management requires a multidisciplinary approach including both medical and surgical therapies. Despite high morbidity With advances in oncologic and end-organ disease treatment, and mortality associated with AIFS [4, 5], there remains no there has been a corresponding rise in the number of immu- standardized protocol for managing this disorder. Here, we nocompromised patients [1, 2]. This has led to an increase in present a comprehensive medical and surgical approach to invasive fungal infections, of which acute invasive fungal si- the diagnosis and management of AIFS in immunocompro- nusitis (AIFS) is a particularly severe form [3]. Optimal mised patients focusing on cancer and transplant patients.

This article is part of the Topical Collection on Transplant and Oncology

* Monica Fung Greg E. Davis [email protected] [email protected]

Jennifer Babik 1 Division of Infectious Diseases, University of California San [email protected] Francisco, San Francisco, CA 94143, USA Ian M. Humphreys 2 Department of Otolaryngology, University of Washington, [email protected] Seattle, WA, USA 53 Page 2 of 11 Curr Infect Dis Rep (2019) 21:53

Definition of AIFS Microbiology

Fungal sinusitis is categorized into non-invasive and invasive The most commonly implicated fungal pathogens in AIFS are forms depending on the presence of fungal invasion into the Aspergillus and Mucorales [5, 8, 9, 11]. Among hematologic submucosa and adjacent vasculature [3, 6]. Non-invasive forms malignancy patients, Aspergillus species tend to predominate include allergic fungal sinusitis and sinus mycetoma (fungal with a prevalence up to 72%, whereas among patients with ball). Invasive fungal sinusitis is further subcategorized into poorly controlled diabetes, the prevalence of mucormycosis chronic and acute forms, both of which occur predominantly in hasbeenreportedupto75%[5, 12]. Atypical fungal patho- patients with some degree of immunocompromise. gens that are less commonly involved include Fusarium, Chronic invasive fungal sinusitis occurs over the course of Scedosporium, Alternaria, Paecilomyces,andScopularopsis months to decades, most often in diabetics or patients on species. It is important to note that prevalence of fungal path- chronic low-dose corticosteroid therapy. These patients often ogens varies by healthcare setting and geographic region de- present with low-grade, non-acute symptoms such as facial pending on local epidemiology and antifungal prophylaxis pain, epistaxis, or nasal congestion with findings of nasal mu- use. Specifically, breakthrough AIFS among patients on azole cosal ulceration and necrosis on examination. prophylaxis is more concerning for infection due to In contrast, AIFS progresses rapidly with a typical time Mucorales spp. and atypical fungal organisms [13, 14]. course of less than 1 month and occurs in patients with more In a study comparing patients with Aspergillus versus severe immunosuppression including hematologic malignan- mucormycosis AIFS, patients with mucormycosis had higher cies, recent chemotherapy, hematopoietic stem cell transplan- mortality (71%) compared with those with Aspergillus (29%) tation (HSCT), solid organ transplantation (SOT), and those though this was notably not statistically significant [15]. In con- with poorly controlled diabetes. Presenting symptoms may trast, another recent study found that patients with AIFS caused include fever and often localize to the paranasal sinuses with by atypical fungi (e.g., non-Aspergillus or Mucorales)hadsig- nasal congestion, facial swelling, rhinorrhea, and facial pain. nificantly poorer survival at 1 month (HR 3.1, p =0.04)[5]. With more extensive disease, visual changes and cranial neu- ropathies can be present. Pathology demonstrates fungal sub- mucosal invasion with associated necrosis of nasal mucosa Clinical Manifestations and underlying bone. The mortality rate of AIFS is reported as high as 50–80% [4, 7, 8]. From here on out, we will focus As AIFS can present in a variety of patterns, it is important to ourdiscussiononAIFS. have a high degree of clinical suspicion in patients from high- risk populations including those with neutropenic fever. Symptoms worrisome for AIFS are similar to those of com- Epidemiology and Risk Factors monly occurring conditions such as viral or bacterial sinusitis. However, the clinical context (e.g., immunocompromised Patients with severe immunosuppression such as those with host) raises the index of suspicion and thus consideration for hematologic malignancies, HSCT, SOT, and poorly controlled AIFS. diabetes account for the majority of cases of AIFS. In a meta- Several studies have shown that patients with AIFS can analysis of 52 publications including 802 patients with AIFS, present with a range of symptoms. Turner et al. found facial diabetes was the most common predisposing condition, occur- swelling, fever, nasal congestion, and eye pain occur in greater ring in nearly half (47.8%) of patients. Others risk factors than 50% of patients [4]. Similarly, Wandell et al. reported included hematologic malignancy (39.0%), corticosteroid facial pain, facial swelling, nasal congestion and fever to be use (27.6%), renal or liver failure (6.6%), SOT (6.3%), HIV/ the most common presenting signs and symptoms. Visual AIDS (2.3%), and autoimmune disease (1.2%) [4]. changes, proptosis, and extraocular muscle weakness are less Among patients with hematologic malignancy, those at common signs, but in these authors’ experience, tend to man- particular increased risk of AIFS are patients with active dis- ifest in more advanced disease [5]. ease, either at onset or relapse, neutropenia, and HSCT [9]. The most common anatomic locations for AIFS to occur While neutropenia with an absolute neutrophil count (ANC) < are the nasal cavity turbinates and paranasal sinuses. Overall, 500 is common among hematology malignancy patients with most cases occur in either the nasal cavity (e.g., septum and AIFS, a recent multi-institutional retrospective review of 114 turbinates) or maxillary sinus. When disease extends beyond AIFS patients found that 52% had an an ANC > 1000 at the the sinuses, it can involve the orbit, cavernous sinus, time of AIFS diagnosis. Among SOT recipients with invasive pterygopalatine fossa, or intracranial space, each with its mold infection, sinus involvement occurred most among renal own anticipated sequelae. Most studies report the orbit as (11%) and liver (3%) transplant recipients compared with tho- the most frequent site of disease extension beyond the sinuses. racic transplant recipients (0%) [10]. Therefore, special attention should be given to any Curr Infect Dis Rep (2019) 21:53 Page 3 of 11 53 ophthalmologic symptoms, especially ophthalmoplegia that inflammatory changes extending beyond the bony boarders tends to be a harbinger of AIFS. Spread to the cavernous sinus of the sinuses could indicated extension of AIFS beyond the and orbit can quickly progress to complications including or- sinuses (Fig. 2)[16]. bital apex syndrome, superior orbital fissure syndrome, or Some authors have proposed MRI as an initial diagnostic tool cavernous sinus syndrome/thrombosis. Intracranial extension for AIFS. However, access to MRI, length of image acquisition will present with altered mental status or cranial neuropathy time, and cost can be limiting [17]. A recent study reported based on the anatomic location of invasion. approximately 50% of AIFS patients had loss of contrast en- hancement on MRI, which may be an early radiographic finding that further supports the need for surgical exploration. Additional Diagnosis data has demonstrated that patients have increased mortality after surgical debridement if they develop new lesions with loss of Physical Exam contrast enhancement (Fig. 3)[18]. If there is suspicion of intra- cranial or intraorbital involvement, CT and MRI are complemen- Evaluation of a patient with suspected AIFS should first begin tary and both studies should be considered. with a comprehensive head and neck exam with particular Beyond dedicated imaging of the sinuses and brain, CT chest attention to the nasal, oral cavity (including teeth and palate), should be considered to assess for concurrent pulmonary infec- soft tissue, ophthalmologic, and cranial nerve assessments. tion, which may offer an additional site for diagnostic sampling. The nasal and oral mucosa should be examined for signs of Pulmonary involvement occurs in the minority of patients with pallor or necrosis, the dentition should be assessed for mobil- AIFS, but portends increased mortality [7, 19, 20]. ity or hypesthesia, and the ophthalmologic exam should detail visual acuity, pupil symmetry, reactivity, gaze mobility, and Histopathology health of the sclera and conjunctiva. A comprehensive cranial nerve exam should be carried out and any deficits or asym- The current gold standard for diagnosing AIFS is evidence of metry noted. If there are abnormalities on any of these exam angioinvasion by hyphal elements on hematoxylin and eosin findings, or if suspicion of AIFS is high, immediate otolaryn- (H&E)–stained anatomic pathology specimens. In a review of gology consultation is advised. 271 biopsies evaluated for AIFS [21], 41 were positive on permanent H&E staining. Of those 41 positive specimens, Nasal Endoscopy 34 were found positive on frozen H&E pathology, whereas 39 were positive on frozen periodic acid-Schiff stain frozen Nasal endoscopy is a valuable tool in the assessment of AIFS. pathology (PASF-Fs). Thus, the addition of PASF improved A detailed endoscopic exam without local anesthesia is critical sensitivity from 85 to 95%. Additional findings of tissue ne- and provides immediate information regarding the health of crosis and branching patterns of the fungal organism are often the mucosal surfaces within the nasal cavity. Signs of pallor or commented on by pathologists familiar with the diagnosis. decreased sensation can be subtle clues that indicate early Intraoperatively, frozen section can support operative signs of AIFS, whereas frank necrosis is a late but typical decision-making as well as confirm the presence of tissue finding. Importantly, when AIFS presents in the paranasal invasion by fungal organisms, especially when frank necrosis sinuses (without nasal cavity involvement), the nasal endos- is not present endoscopically. Gomori methenamine silver copy may show normal healthy mucosa as the sinus proper (GMS) stain is a useful tool in the histologic visualization of may not be visualized; therefore, a negative nasal endoscopy fungi as well, and can confirm the presence of fungal organ- does not preclude the diagnosis of AIFS. Given this limitation isms seen within tissue on H&E stains. of nasal endoscopy, radiographic imaging is a complimentary and equally important diagnostic tool. Fungal Markers

Radiology The use of the serum Aspergillus galactomannan assay (GM) can be a helpful component in the diagnosis of invasive Computed tomography (CT) and magnetic resonance imaging Aspergillus infections, although with imperfect sensitivity (MRI) are the most frequently used forms of imaging for and specificity [22]. There are only a few small studies eval- AIFS. Overall, CT is the most common and provides helpful, uating the use of serum GM in AIFS, where it was found to be quick, non-invasive information regarding bone integrity < 50% sensitive for the diagnosis of Aspergillus AIFS; in around the sinuses, orbits, and skull base. If CT demonstrates addition, false-positives were common due to cross- bony erosion or evidence of soft tissue extension of paranasal reactivity with other fungal causes of AIFS [11, 23, 24]. sinus disease (Fig. 1), suspicion for AIFS must remain high. Another serum fungal marker, beta-D-glucan, is a component Additionally, fat stranding, loss of fat planes, and of most fungal cell walls, although mucormycosis is a notable 53 Page 4 of 11 Curr Infect Dis Rep (2019) 21:53

Fig. 1 a Coronal non-contrast CT demonstrating left inferior turbinate Intraoperative view after turbinate resection (arrow); note that residual demineralization (arrow) and soft tissue thickening. b Intraoperative areas of black tissue are from cautery effect and not necrosis endoscopic view of necrotic left inferior turbinate (arrow). c exception. While this test is sometimes used in the diagnosis have higher yield and are positive in anywhere from 50 to of invasive Aspergillosis with modest sensitivity and specific- 95% of cases [11, 26–28]. ity [25], there is a paucity of data on its use in AIFS. Taken Molecular diagnostics are a promising new tool for together, serum fungal markers may be a helpful adjunct in diagnosis of invasive fungal infections, including AIFS. diagnosis, especially for Aspergillus AIFS, but it is critical to Recent data indicate that species-specific PCR (for recognize that their sensitivity is poor and negative testing Aspergillus or Mucorales) and broad-range panfungal does not exclude a diagnosis of AIFS. PCR can increase the diagnostic sensitivity to > 70–80% and potentially even decrease time to diagnosis [27–29]. Unfortunately, these techniques are often only available at Microbiology tertiary research medical centers and generally do not have FDA approval. One additional downside to making As opposed to histopathology stains, fungal stains per- a diagnosis solely by PCR is the lack of antifungal sus- formed on tissue specimens in the microbiology laboratory ceptibility information, although identification to the spe- are positive in the minority (~ 30%) of cases [11]. Cultures cies level can help guide antifungal stepdown therapy based on published minimum inhibitory concentration (MIC) data. Regardless of technique used for fungal iden- tification, specimens should be sent for antifungal resis- tance testing to appropriately target systemic therapy.

Definition

As with other invasive fungal infections, it is important to appropriately categorize AIFS cases as proven versus probable invasive mold infection based on the 2008 European Organization for Research and Treatment of Cancer criteria [30].

Medical Management

There are three pillars in the treatment of invasive AIFS: (1) urgent surgical debridement, (2) antifungal therapy, and (3) reversal of immunosuppression. Optimal management re- Fig. 2 Non-contrast axial CT demonstrating total opacification of the quires a multidisciplinary approach with Infectious Disease right maxillary sinus with demineralization and defects in the posterior- and Otolaryngology input, as well as other potential special- lateral maxillary sinus wall in a patient with AIFS. Note the loss of the fat plane posterior to the maxillary sinus indicating an infectious/ ists (ophthalmology, neurosurgery) depending on extent of inflammatory process infection. Curr Infect Dis Rep (2019) 21:53 Page 5 of 11 53

Fig. 3 MRI changes associated with AIFS. a Axial T1-weighted MRI demonstrates an isointense lesion within the superior aspect of the sphenoid sinus. b Axial T1- weighted fat-suppressed contrast- enhanced image shows similar lesion as in a and demonstrates loss of contrast enhancement

Antifungal Therapy predictive of clinical treatment success, with a trough < 1 asso- ciated with failure and >2 mg/L is recommended for severe Empiric Therapy Empiric antifungal therapy should be started infections [36, 37]. Doses should be adjusted to maintain levels immediately as soon as there is clinical suspicion for AIFS; delay < 5.5 mg/L to reduce voriconazole toxicity, including vision in therapy of ≥ 6 days is associated with a twofold increase in changes and hallucinations. Posaconazole levels > 1.0 mg/L mortality [31]. For all patients, including those on azole prophy- should be targeted for treatment. In contrast, clinical evidence laxis, the authors recommend initial empiric therapy with liposo- has not demonstrated a relationship between isavuconazole level mal amphotericin B, which is active against mucormycosis as and efficacy or safety, though some experts recommend thera- noted below. Once a causative organism has been identified, peutic drug monitoring to ensure patient does not fall into 10% targeted antifungal therapy should be initiated (Fig. 4). who have levels < 1 mg/L. [38] The Clinical & Laboratory Standards Institute and Targeted Therapy for Aspergillus The three main classes of European Committee on Antimicrobial Susceptibility antifungal agents for the treatment of invasive Aspergillosis Testing have established clinical breakpoints for voriconazole, are the polyenes, the triazoles, and the echinocandins. itraconazole, and posaconazole against Aspergillus spp., and Voriconazole is a first-line therapy with isavuconazole and epidemiologic cutoff values and wild-type distributions for liposomal amphotericin B considered alternative agents isavuconazole and echinocandins. Overall, voriconazole and [32–34]. Posaconazole has been used for treatment in cases isavuconazole exhibit reduced efficacy against Aspergillus refractory or intolerant of first-line therapy. In contrast, isolates with MICs ≥ 16 μg/mL, including non-fumigatus echinocandins should only be considered as part of combina- Aspergillus species such as A. ustus and A. niger [39]. tion therapy or salvage therapy [33, 34]. Below this threshold, there is limited understanding about Combination antifungal therapy for invasive Aspergillosis susceptibility and clinical outcomes. Of note, recent evidence is not routinely recommended, but can be considered for sal- indicates there is increasing prevalence of azole-resistant iso- vage therapy or in very severe cases. In a randomized con- lates in the environment. A global survey reported that 3.2% trolled trial of combination therapy of voriconazole plus of Aspergillus isolates are azole-resistant, with notably higher anidulafungin versus voriconazole alone among 454 hemato- resistance rates in certain European countries [40]. Liposomal logic malignancy patients, there was a trend toward decreased amphotericin B–based or combination regimens are recom- mortality (p = 0.09) in the combination therapy group with mended for patients with azole resistance. similar safety profile [35]. Combination antifungal therapy with triazole and echinocandin as well as liposomal Targeted Therapy for Mucorales Liposomal amphotericin B is amphotericin and echinocandin has been used, but triazole the initial drug of choice for AIFS caused by Mucorales.The and liposomal amphotericin are often favored for central ner- optimal dose of liposomal amphotericin has not been vous system infections [33, 34]. established in randomized clinical trials. Preclinical data sug- Therapeutic drug monitoring should be performed for all pa- gested that higher doses (e.g., 10 mg/kg) of liposomal tients on azole antifungals, particularly when there is concern amphotericin might be needed to treat invasive mucormycosis about gastrointestinal absorption, clinical or laboratory evidence [41]. However, in the AmBizygo trial, a prospective trial of of toxicity, co-administration of interacting drugs, and severe liposomal amphotericin at 10 mg/kg/day for treatment of pa- disease. Therapeutic voriconazole serum concentrations are tients with mucormycosis, there was no survival benefit 53 Page 6 of 11 Curr Infect Dis Rep (2019) 21:53

Fig. 4 Acute invasive fungal sinusitis medical management algorithm

compared with historical controls and patients had high rates There is significant debate over the benefit of combination of nephrotoxicity [42]. The most recent guidelines from the therapy in the initial treatment of mucormycosis. A small retro- European Conference on Infections in Leukemia recommend spective study in 2008 showed a survival benefit for combination starting liposomal amphotericin at a dose of 5 mg/kg/day [43], therapy with amphotericin and an echinocandin compared with as do other experts within the USA [44].Adoseincreasecan amphotericin alone, although the number in the combination be considered in patients failing standard therapy and/or who group was small [47]. However, a larger retrospective study in have significant central nervous system involvement [44]. 2016 showed no survival benefit with this combination [48]. For patients who are intolerant or refractory to liposomal There is also interest in using an azole with activity against amphotericin, isavuconazole and posaconazole are both po- mucormycosis (posaconazole or isavuconazole) as the drug to tential options with activity against Mucorales spp. While use in combination with amphotericin. The benefit of such a both drugs have been shown to be effective as salvage therapy strategy remains unclear, as a small retrospective study of [45, 46], only isavuconazole has been shown, in a small num- posaconazole plus amphotericin as salvage therapy did not show ber of patients in the VITAL study, to be effective as primary a survival benefit compared with historical controls treated with treatment for mucormycosis [46]. amphotericin monotherapy [49]. One benefit of early Curr Infect Dis Rep (2019) 21:53 Page 7 of 11 53 combination therapy with an azole is that if patients are intolerant Alternative Therapies of liposomal amphotericin, this can be held or stopped and the patient will still be on active therapy, without needing to wait Given increased risk for AIFS among patients with hemato- several days to reach steady-state levels if an azole was only logic malignancy with neutropenia, granulocyte transfusion started at that point. has been used in select cases. A recent multi-institutional re- Induction therapy with liposomal amphotericin is usually view of 114 patients with AIFS showed that immune- continued for at least 3 weeks [44] before stepping down to an stimulating therapies (G-CSF, GM-CSF, granulocyte transfu- oral azole. Oral azole therapy is then continued for a sion, or a combination of these) resulted in a 70% reduction in prolonged duration of therapy, at least 3–6months[45, 46] 1-month mortality [5]. and often much longer depending on the immune status of the Case reports and series have reported survival benefit in patient (e.g., if immunosuppression is reversible). The deci- patients with AIFS rhinosinusitis treated with hyperbaric ox- sion as to which azole for stepdown therapy should be made ygen [55, 56] with the theory that hyperbaric oxygen im- on an individual basis, taking into consideration the side effect proves blood flow to ischemic tissues and acidosis. Other profile of the drugs (e.g., isavuconazole does not prolong the studies, however, have noted increased mortality among pa- QT interval), need to monitor levels (e.g., there is more data tients who received hyperbaric oxygen [15]. Overall, addition- and clinical experience for therapeutic drug monitoring with al studies are needed to better clarify the role of these alterna- posaconazole), fungal MICs if available (although these are tive therapies in AIFS and other invasive fungal infections. not clearly associated with outcomes), and whether or not there is concern for development of breakthrough invasive fungal infections while on chronic azole therapy. This latter Surgical Management point is notable since isavuconazole has recently been linked to breakthrough fungal infections, in particular in patients who Surgical Candidacy are solid organ transplant or hematologic malignancy patients [14, 50]. Whether to take a patient with suspected AIFS to the operating room (OR) is a critical decision that needs to be made by a AIFS Due to Other Organisms AIFS caused by rare or atypical multidisciplinary team made up of surgeons, Infectious fungal pathogens such as Fusarium, Scedosporium, Disease specialists, and the patient’s primary providers (e.g., Alternaria, Paecilomyces,andScopularopsis species should oncologist, transplant specialist, endocrinologist depending be treated in conjunction with an Infectious Diseases specialist on patient’s underlying immunosuppression). and guided by existing expert consensus guidelines [51]. Surgeons should first assess if the patient is a surgical candi- date. Occasionally, patients are too sick or debilitated to be Duration of Therapy The optimal duration of antifungal ther- deemed proper candidates for general anesthesia, or their under- apy for AIFS should be individualized based on response to lying disease has progressed beyond a reasonable chance for therapy, both clinical and radiological, and patient’sunderly- improvement. Performing a bedside biopsy is possible, but there ing immune status. At minimum, therapy should be continued are significant limitations to the anatomic structures that can be until all clinical and radiologic abnormalities have resolved biopsied in an awake, inflamed patient, namely only the anterior and until no microbiologic evidence of infection (normaliza- portions of the inferior and middle turbinate or the nasal septum. tion of fungal biomarkers, negative cultures if resampling oc- If suspected AIFS disease is present within a sinus, or more curs). In an epidemiologic study of 89 hematologic malignan- posteriorly, these areas require sinus surgery to access for biopsy. cy patients with CNS and sinus invasive fungal infection, Additionally, bedside biopsies run the risk of sampling error— median duration of antifungal therapy was 60 days (range 5– missing the diseased tissue entirely or taking a biopsy of necrotic/ 835) [9]. non-viable tissue that cannot be properly interpreted by patholo- gy. Because of these reasons, the authors’ algorithm guiding Reversal of Immunosuppression surgical decision-making in these complex patients discourages the use of bedside biopsies (Fig. 5). Reversing underlying disease process and decreasing immu- Once the decision is made to go to the OR, the next critical nosuppression is a mainstay of treatment in patients with decision relates to timing of the procedure. Certainly, if there is AIFS, playing as an important role as surgical management evidence of an impending complication such as vision loss, and antifungal therapy [52, 53]. In a case series of 7 hemato- prompt surgical intervention is important. If the clinical presen- logic malignancy patients with AIFS, 5 were treated with tation is less concerning, it is often preferred to perform surgery combined medical and surgical therapy, of which only three when the patient is optimized and the proper surgical team is survived—all three demonstrated substantial improvement af- available. One study examining the urgency of surgery for ter neutrophil recovery [54]. AIFS found that surgical intervention within 6 days of 53 Page 8 of 11 Curr Infect Dis Rep (2019) 21:53

Fig. 5 Acute invasive fungal sinusitis surgical management algorithm presentation of clinical symptoms led to improved survival com- Operative Technique pared to surgical intervention between 7 and 12 days or > 13 days [55]. The initial steps of operative intervention involve relatively Prior to surgery, it is important to ensure appropriate imag- routine sinus surgery with the primary goal of establishing a ing (e.g., CT maxillofacial and/or MRI with gadolinium par- definitive diagnosis by obtaining representative diseased tis- ticularly if cranial neuropathies or ophthalmologic signs or sue for histopathologic analysis, pathogen identification, and symptoms present) has been obtained and patient has been tissue cultures that permit antifungal sensitivity analysis. properly prepared for surgery including NPO status and rever- Tissue immediately adjacent to the areas of necrosis often sal of coagulopathy. Thrombocytopenia is common in patients yields superior H&E results compared with examining frankly with AIFS, and we recommend a target of at least 50,000 per necrotic tissue. Secondary objectives include removing all ne- microliter prior to surgical intervention. crotic tissue and opening up any obstructed sinuses. If sub- Curr Infect Dis Rep (2019) 21:53 Page 9 of 11 53 total resection of necrotic tissue is performed, then revision Conclusion surgery should be considered in the near future by a qualified surgeon comfortable with advanced rhinologic procedures. Despite improvements in medical and surgical manage- ment of AIFS, mortality continues to approach 50%. Early diagnosis of this disease entity followed by aggres- Neurosurgical and Ophthalmology Involvement sive surgical and medical management are important. However, reversal of the underlying source for immuno- Due to the complex nature of head and neck anatomy, the suppression is likely the primary predictor of survival. disease process of AIFS often extends to places that require Immune-stimulating therapies may improve short-term the expertise of several different specialists. When there is survival, but require additional study. concern for optic or orbit involvement, ophthalmology should be consulted. If there is concern for intracranial involvement, Compliance with Ethical Standards neurosurgery should be consulted. Additionally, if the teeth are found to be involved (loose dentition), oral surgery should Conflict of Interest All authors declare no conflict of interest. be consulted. Kennedy et al. reported survival did not improve if aggres- Human and Animal Rights and Informed Consent This article does not “ ” contain any studies with human or animal subjects performed by any of sive debridement of tissue is performed outside the box of the authors. the sinonasal cavity [57]. Specifically, if there is intracranial involvement, it would be uncommon for a neurosurgeon to recommend surgical debridement. Similarly, if vision loss has References occurred, it is uncommon for an ophthalmologist to recom- mend initial orbit exenteration. Delayed exenteration may be 1. Wilson AL, Plebanski M, Stephens AN. New trends in anti-cancer needed to alleviate ophthalmoplegia or as part of an approach therapy: combining conventional chemotherapeutics with novel im- – for palliation of pain. munomodulators. Curr Med Chem. 2018;25(36):4758 84. https:// doi.org/10.2174/0929867324666170830094922. 2. 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